POST‐TREATMENT PET‐CT RATHER THAN INTERIM...

POST‐TREATMENT PET‐CT RATHER THAN INTERIM PET‐CT USING

DEAUVILLE CRITERIA PREDICTS OUTCOME IN PEDIATRIC HODGKIN

LYMPHOMA: A PROSPECTIVE STUDY COMPARING PET‐CT VERSUS

CONVENTIONAL IMAGING

Sameer Bakhshi1, Sainath Bhethanabhotla1, Rakesh Kumar2, Krishankant Agarwal2,

Punit Sharma2, Sanjay Thulkar3, Arun Malhotra2, Deepa Dhawan1, Sreenivas Vishnubhatla4

Department of Medical Oncology, Dr. B. R.A. Institute Rotary Cancer Hospital, All India

Institute of Medical Sciences, New Delhi, INDIA1

Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi,

INDIA2

Department of Radiology, Dr. B. R.A. Institute Rotary Cancer Hospital, All India

Institute of Medical Sciences, New Delhi, INDIA3

Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, INDIA4

Corresponding Author:

Dr. Sameer Bakhshi Professor of Pediatric Oncology Department of Medical Oncology, Dr. B. R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences New Delhi‐110 029, INDIA Email: [email protected]

Tel# 91‐11‐26589200 Ext 5237, 91‐11‐26588153 Fax # 91‐11‐26588663

Word Count: 3009 Abstract word count: 300 Tables: 5 Figures: 3 Supplement Table: 1 Supplementary Figures: 4

Funding: Department of Biotechnology, Government of India

Running Title: Significance of PET‐CT in Pediatric HL

Journal of Nuclear Medicine, published on October 6, 2016 as doi:10.2967/jnumed.116.176511by on May 8, 2018. For personal use only. jnm.snmjournals.org Downloaded from

http://jnm.snmjournals.org/

ABSTRACT

Background

Data about significance of 18F‐FDG positron emission tomography (PET) at interim assessment

and end of treatment in pediatric Hodgkin lymphoma (HL) are limited.

Methods

Patients (≤18 years) with HL were prospectively evaluated with contrast‐enhanced

computed tomography (CECT) and PET combined with low‐dose CT(PET‐CT) at baseline, post 2

cycles of chemotherapy and post completion of treatment. Revised international working group

criteria (RIW) and Deauville five point‐scale for response assessment by PET‐CT were used. All

patients received ABVD chemotherapy along with involved field radiotherapy (25 Gy) for early

stage (IA, IB and IIA) and advanced stage (IIB‐IV) with bulky disease.

Results

Of the 57 enrolled patients, median follow‐up was 81.6 months (range: 11‐97.5

months). Treatment decisions were based on CECT. At baseline, PET‐CT vs CECT identified 67

more disease sites; 23 patients (40.3%) were upstaged and of them in 9 patients (39%)

upstaging would have affected treatment decision; notably none of these patients relapsed.

Specificity of interim PET‐CT based on RIW (61.5%) and Deauville (91.4%) criteria for predicting

relapse was higher than CECT (40.3%) (p=0.03 and p<0.0001 respectively). Event free survival

(EFS) based on interim PET‐CT response (positive vs. negative scan: 93.3±4.1 vs. 89.6±3.8;

p=0.44). Specificity of post‐treatment PET‐CT (Deauville) was 95.7% vs. 76.4% by CECT

(p=0.006). Post‐treatment PET‐CT (Deauville) showed significantly inferior overall survival (OS)

in patients with positive scan vs. negative scan (66.4±22.5 vs. 94.5±2.0, p=0.029).

Conclusion

Interim PET‐CT has better specificity and use of Deauville criteria further improves it.

Escalation of therapy based on interim PET in pediatric HL needs further conclusive evidence to

justify its use. Post‐treatment PET‐CT (Deauville) predicts OS and has better specificity in

comparison to conventional imaging.

Key Words: PET‐CT, Pediatric Hodgkin lymphoma, CECT

by on May 8, 2018. For personal use only. jnm.snmjournals.org Downloaded from


INTRODUCTION

Pediatric Hodgkin lymphoma is a malignancy with high cure rates with currently available

combined modality treatment (chemotherapy and radiotherapy)1. The current emphasis is to

identify patients with high risk of relapse and to minimize the long‐term side effects in the

survivors. A risk‐adapted treatment approach based on interim response assessment with

positron emission tomography combined with computed tomography is advocated in adult

patients with HL for this purpose2. Studies in adult patients with HL have shown that a positive

interim PET‐CT scan predicts higher chance of relapse and poor outcome3,4.

Contrast‐enhanced computed tomography has been conventionally used for staging and

response assessment for children with HL. It is easily available, affordable and reproducible

investigation for staging and response assessment. The evidence for the role of PET‐CT imaging

in pediatric HL in evaluation, response assessment and prognostic value is limited and

predominantly retrospective in nature5–9.

Two prospective studies in small number of subjects have shown conflicting results. A

study by Furth et al10 has demonstrated that interim PET‐CT had excellent negative predictive

value (NPV) but a poor positive predictive(PPV) for relapse. Another study by Ilivitzki et al11

showed higher PPV for interim PET‐CT. Notably, the criteria for response assessment by PET‐CT

were different in both the studies. The prognostic impact of interim and post‐treatment PET‐CT

on event free survival and overall survival was also not reported in these studies. We

prospectively studied the role of combined 18F‐FDG ‐PET‐CT compared with CECT alone in

identifying patients with residual disease and its prognostic significance to predict relapse in

pediatric HL.

MATERIALS AND METHODS

Study Objective

The primary objective was to evaluate the sensitivity, specificity, PPV and NPV of interim

and post‐treatment PET‐CT as compared to CECT alone in pediatric HL patients in predicting

relapse. The secondary objective was to determine the prognostic significance of a positive

PET‐CT at interim assessment and post treatment on EFS and OS.

Study Design

This was a prospective study in children with HL treated with a uniform protocol and

compared baseline, interim and post treatment scans of CECT and PET‐CT.

Participants



We prospectively enrolled children (age ≤18 yr) diagnosed with HL attending the

oncology clinic at our centre from January 2008‐December 2010. The study was carried out as

per the guidelines of Declaration of Helsinki, after approval by Institute ethics committee.

Written informed consent was taken from parents and/or child before enrollment into the

study. All patients were enrolled after establishing tissue diagnosis. Other investigations apart

from CECT and PET‐CT included complete blood counts, erythrocyte sedimentation rate, serum

lactate dehydrogenase levels, liver and renal function tests, and bone marrow aspiration and

biopsy. Modified Ann Arbor classification was used for staging12.

Treatment And Response Assessment

All patients were treated with standard doxorubicin, bleomycin, vinblastine and

dacarbazine chemotherapy13. Patients in early stage (stage 1A, 1B and 2A) received 4 cycles of

chemotherapy. Patient with advanced stage (Stage 2B, 3 and 4) received 6 to 8 cycles of

chemotherapy. All early stage patients and advanced stage with bulky disease received low

dose involved field radiotherapy (25 Gy in 15 fractions). Notably, all patients were treated

based on baseline CECT staging irrespective of PET‐CT staging.

Patients underwent whole body PET‐CT and CECT of neck, chest, abdomen and pelvis at

baseline for staging (PET‐1 and CT‐1), after 2 cycles of chemotherapy for interim assessment

(PET‐2 and CT‐2) and after completion of chemotherapy (PET‐3 and CT‐3). Scans were obtained

atleast 2 weeks after chemotherapy cycle.

CECT Acquisition And Analysis

CECT of neck, chest and abdomen were done on 64 slice MDCT (Definition AS, Siemens,

Germany). All patients were given oral contrast (2% iomeprol) 500‐1000 ml divided at 45 min

and 15 min before scan. Intravenous non ionic contrast (iomeprol, 400 mg/ml) was injected as

bolus prior to the scan at a dose of 2 ml/kg. Sections of 5 mm were taken from below base of

skull up to pelvic floor.

An experienced radiologist (ST) prospectively reviewed all CECT scans on work station.

Response was defined on CECT as complete response , partial response , stable disease and

progressive disease based on revised International working group response criteria14.

18F‐FDG PET‐CT Acquisition Protocol

All patients received intravenous injection of 6–7 MBq/kg (minimum 110 MBq and

maximum 370 MBq) of 18F‐FDG. PET‐CT imaging was performed after 45–60 min of injection.

PET‐CT acquisition was performed on a dedicated PET‐CT scanner (Biograph 2; Siemens Medical

Solutions, Erlangen, Germany). For the CT part of PET‐CT, no oral or intravenous contrast agent



was administered. CT was acquired on a spiral‐dual section method with following

parameters—slice thickness of 4 mm, pitch of 1, matrix of 512x512 pixels and pixel size of 1

mm. After completion of CT acquisition, acquisition of PET was carried out in same axial range

with patient in same position. Three‐dimensional PET acquisition was performed for 2–3 min

per bed position, with a matrix of 128x128 pixels and slice thickness of 1.5mm. CT‐based

attenuation correction of PET emission images was performed. PET images were reconstructed

by an iterative method with ordered subset expectation maximization algorithm (two iterations

and eight subsets). The reconstructed attenuation‐corrected PET images, CT images and fused

PET‐CT images were available for review in axial, coronal and sagittal planes, along with

maximum intensity projections and three‐dimensional cine mode.

18F‐FDG PET‐CT Image Analysis Using Revised International Working Group (RIW)

Response Criteria

18F‐FDG PET‐CT was evaluated by two nuclear medicine physicians (RK and AM with 10

years experience in PET‐CT imaging). Any positive findings on 18F‐FDG PET were localized

anatomically on non‐enhanced CT. All patients were assessed for response as Complete

response, partial response, stable disease and progressive disease based on RIW response

criteria14.

Nuclear physician (RK and AM) was blinded to the clinical details and radiological response of

patients.

18F‐FDG PET/CT Image Analysis Using Deauville Criteria (DC): Retrospectively

Analyzed

At the beginning of study, RIW response criteria were considered for image analyses.

Later studies in adult patients with HL showed predictive role of interim PET‐CT assessment on

survival using Deauville five point‐ scale15. Thus, additionally, we retrospectively reviewed PET‐

CT images of all patients by two experienced nuclear medicine physicians (RK and KK) with

more than 10 and 5 years experience in oncological PET‐CT imaging respectively. Both of them

were blinded regarding patient details, outcomes, and CECT findings. Further, the two

physicians (RK and KK) independently reviewed the PET‐CT images, and wherever there was

discrepancy in findings, a consensus was reached with mutual discussion.

For assessment of treatment response, the following definitions were used; Complete

response: Deauville scores 1, 2 or 3 together with absence of 18F‐FDG avid bone marrow

lesions irrespective of a persistent mass on CT; Partial response: Deauville score 4 or 5, but

uptake is decreased compared to baseline and absence of structural progression on CT; Stable

disease: no metabolic response, Deauville score 4 or 5, with no significant change in 18F‐FDG



uptake from baseline; and Progressive disease: Deauville score 4 or 5 with increasing intensity

compared to baseline or any new 18F‐FDG avid lesions.

Statistical Analysis

SPSS software (version 16.0; SPSS Inc, Chicago, IL) was used for data analyses.

Sensitivity, specificity, positive predictive value and negative predictive value were calculated

using standard formulas. Kaplan Meier survival analysis was used to determine EFS and OS.

Data was censored on 31, December 2015. OS was calculated from data of diagnosis to death

due to any cause. EFS was calculated from date of diagnosis to date of relapse or death due to

any cause. McNemar test with continuity correction was used for comparison of proportion of

negative findings with each imaging modality. Kappa statistic was used to measure degree of

agreement between investigators (R.K and KK) for using Deauville criteria for PET‐CT images.

RESULTS

Fifty‐seven consecutive patients of pediatric HL were enrolled in study and their

baseline characteristics are shown in Table 1. Their staging by CECT and PET‐CT, response and

final status is shown in Supplementary Table 1. Median follow‐up of the cohort was 81.6

months (range: 11‐97.5 months). One patient in complete response was lost to follow‐up after

18 months (patient no. 31). Four patients relapsed during follow‐up of whom two are currently

doing well and disease free after salvage therapy (patient no. 30 and 36). There were three

deaths of whom two patients died due to disease progression (patient no.17 and 35) and one

patient died of treatment‐related pulmonary toxicity (patient no.57) (Supplementary Table 1).

The mean interval between CT and PET CT was 10.8 days (Median: 10; Range: 0‐26) at baseline,

4 days (Median: 2; Range: 0‐20) at interim assessment and 6 days (Median: 3; Range: 0‐26) at

the end of treatment.

Baseline Imaging

A total of 219 disease sites were detected with PET‐CT vs. 152 sites with CECT scan.

Sixty‐seven more disease sites were detected in 29 patients with baseline PET‐CT while PET‐CT

showed four less disease sites in three patients. Overall, 23 (40.3%) patients were up‐staged

while four (7%) were down‐staged as per PET‐CT results when compared with the baseline

staging by CECT. Of the 23 patients who were upstaged on PET‐CT, the upstaging would have

affected treatment decision in nine (39%) patients.

Bone marrow and bone involvement was detected by PET‐CT at baseline in six and

twelve patients respectively. Bone marrow biopsy, however, could confirm disease

involvement in only two patients.



Impact Of Change Of Baseline Staging By PET‐CT On Outcome

Of 23 patients who were upstaged by baseline PET‐CT baseline, one patient relapsed

(patient no.35). However, in this patient the upstaging would not have changed the initial

planned treatment as per CT imaging.

Interim Response Assessment [PET‐2 (RIW) vs. CT‐2]

Interim response assessment was done in all patients. The sensitivity and specificity of

positive PET‐2 for predicting relapse is 25% and 61.5% respectively (Table 2). There was a

significant difference between the number of patients who had a complete response on PET‐2

(RIW) vs. CT‐2, [36 (63.1%) vs. 23 (40.3%); p=0.012]. The specificity of positive PET‐2 (RIW) for

relapse was significantly better than CT‐2 (61.5 vs. 40.3, p=0.03). However, the NPV at PET‐2

(RIW) was similar to CT‐2 (91.4% vs. 95.4%, p=0.39). Both the modalities had a low PPV for

relapse.

The difference in EFS and OS of patients with positive and negative PET‐2 scans (Figs. 1A

and 1B) or achievement of complete response on CT‐2 at interim assessment was not

statistically significant (Figs. 1C and 1D) (Table 3).

Post Treatment Response Assessment [PET‐3(RIW) VS. CT‐3]

Fifty‐five patients were tested with both modalities at treatment completion. Post

treatment PET‐3 and CT‐3 could not be done in two and one patient respectively. There was no

significant difference in the proportion of patients attaining complete response in PET‐3 and CT‐

3(83.9% vs. 75%, p=0.24). The sensitivity and specificity of PET‐3 (RIW) was 25% and 88%

respectively (Table 4). No statistically significant differences in sensitivity, specificity, PPV and

NPV were observed between PET‐3 (RIW) and CT‐3 (Table 4).

At the end of treatment, PET‐3 (RIW) was positive in seven patients (four patients had

PD and three patients had partial response). Of the four patients with PD in PET‐3, one had

primary refractory disease, two patients had false positive (one patient had normal findings on

fine needle aspiration cytology of involved lymph node and in the other image guided cytology

was not feasible but on subsequent imaging attained complete response) and showed

tuberculosis in one patient. All the patients who had partial response at PET‐3 were followed up

with repeat imaging and were disease free subsequently.

There was no significant difference in the EFS and OS in patients who had positive PET‐3

(RIW) (Figs. 2A and 2B) or residual disease in CT‐3 (Figs. 2C and 2D) (Table 5)

Retrospective Analysis Using Deauville Criteria For PET‐CT Image Analysis



Deauville criteria was used independently by two nuclear physicians (RK and KK) after

retrieval of the scans (n=53/57 for interim assessment and 52/57 for post‐treatment scans).

There was substantial agreement between both reviewers (RK and KK) in applying the Deauville

score. The weighted kappa for the agreement between the reviewers for the score was 0.58.

However the agreement for the response assessment based on the score (complete response

vs. partial response) was substantially higher (Kappa‐0.84).

Impact Of PET‐CT (Deauville) On Specificity, Sensitivity, PPV And NPV

At interim assessment, when Deauville criteria was used, the specificity of PET‐2

(Deauville) improved when compared to CT‐2 (91.4% vs. 42.6%, p<0.0001). The proportion of

patients attaining CR based on Deauville criteria was also significantly higher in PET‐2

(Deauville) as compared to CT‐2 [49 (92.4%) vs. 23 (40.3%); p <0.0001] (Table 2).

In PET‐3 (Deauville), the proportion of patients attaining complete response (94.2% vs.

75.4%, p=0.007) and specificity was significantly better than CT‐3 (95.7 vs. 76.4, p=0.006) (Table

4).

Impact Of PET‐CT (Deauville) On EFS And OS

The EFS and OS did not differ in patients who were positive or negative by PET‐2

(Deauville) (Figs. 3A and 3B) (Table 3). The EFS between patients who were positive or negative

by PET‐3 (Deauville) was statistically insignificant (Fig. 3C); however, the OS between these two

groups showed a significant difference for poor survival in the group positive by PET‐3

(Deauville) (p=0.029) (Fig. 3D) (Table 5).

DISCUSSION

Our study categorically demonstrated that PET‐CT detected more sites than CECT at

baseline. Although in this study, the treatment decisions were based on CECT staging, PET‐CT

staging would have potentially intensified the treatment in 9 (15.8%) patients (one‐third of the

up‐staged patients). Our study was not designed to detect the benefit or toxicity based on

alteration of treatment based on PET‐CT staging. It is, however, worth noting that none of the

nine patients in whom treatment would have been intensified based on baseline PET‐CT staging

relapsed. Previous studies in pediatric patients have shown similar upstaging in the range of 9‐

50% based on PET6,7,10,16,17. However all these studies were retrospective and the impact of

treatment modification was not studied in any of them.

In our study, the sensitivity of interim PET‐CT was low and a positive PET‐CT at interim

assessment did not have a significant impact on EFS and OS. However, our study showed that

interim PET‐CT has significant specificity as compared to conventional imaging. A few



retrospective studies have shown high sensitivity of interim PET assessment; however, these

studies were limited by the small number of subjects and lack of uniform response assessment

criteria5,8,10.

A prospective study by Furth et al10 used mediastinal blood pool as reference for PET

positivity similar to RIW criteria used in our study; both these methods are subjective in nature.

Deauville criteria have recently been adopted for pediatric NHL response assessment as

well18.It is noteworthy that application of the Deauville criteria increased the specificity of PET‐

CT in our cohort. Hence the use of these criteria as compared to criteria used in study by Furth

et al and RIW criteria used in current study imparts objectivity and reproducibility for PET‐CT

assessment.

The prognostic value of interim PET‐CT could not be established in our study. Previous

COG study used interim response based on CECT (AHOD0031 trial) for treatment de‐escalation;

it was concluded that in early responders, treatment de‐escalation could be done without

compromising efficacy19. This AHOD0031 trial, patients who were slow responders and had

interim PET positivity benefitted marginally with treatment escalation. However, in our study 3

of the 4 patients who relapsed had a negative interim PET‐CT based on both the criteria (RIW

and Deauville). The limitation of AHOD0031 trial is the PET positivity was based on reference

uptake with mediastinal blood pool and the study was not powered to address effect of

treatment escalation based on PET positivity. Notably in our cohort, based on PET‐CT (RIW)

interim assessment, we would have potentially escalated treatment in 21/57 (36.8%) patients

to prevent one relapse; based on Deauville criteria, we would have escalated therapy in 4/52

(7.6%) patients and none would have benefitted. Therefore, we do not recommend treatment

escalation based on interim PET‐CT assessment by either RIW or Deauville criteria.

Post‐treatment evaluation by conventional imaging and PET‐CT (RIW) were similar for

sensitivity and specificity, and in predicting EFS or OS. However, PET‐CT (Deauville) revealed a

significantly improved specificity and PPV for PET‐CT as compared to conventional CECT

imaging. However a tissue diagnosis is mandatory to rule out an infectious etiology as 1/3

patients with positive PET‐CT (Deauville) had underlying infection in our cohort. Further, there

was a trend towards inferior EFS and a significantly inferior OS in patients who had a positive

PET‐CT (Deauville) at the end of treatment. Thus the use of Deauville criteria improved the PPV

and decreased false positivity in comparison to RIW criteria and the criteria used in previous

studies8,10.

The role of histology subtype in interpretation of interim PET‐CT requires further studies

as the relative cellular and sclerosis component differs in the histological subtypes. This could

possibly also explain the different findings in the study by Furth et al when compared to our



study. Mixed cellularity subtype and Epstein Barr virus positivity is higher in our population as

compared to the western population20,21.

The major strength of our study is adequate follow‐up duration, direct comparison of

CECT and PET‐CT modalities by both RIW and Deauville criteria and PET‐CT response

assessment by two experienced nuclear medicine specialists who had good agreement on

assessment. Further studies based on Deauville criteria for PET‐CT interpretation can bring

uniformity for trial comparisons and to identify patients with high risk of relapse.

CONCLUSION

To conclude, baseline imaging with PET‐CT may potentially affect the treatment decision

which may not prevent relapse or prolong survival. So, further studies to evaluate the role of

baseline imaging with PET‐CT are needed. Our study shows that there is no conclusive evidence

for PET‐based risk stratification for escalation or de‐escalation of therapy. Escalation of therapy

based on interim PET in pediatric HL needs further conclusive evidence to justify its use; this is

even more relevant in HL as compared to other malignancies as majority of patients can be

salvaged at relapse. Post treatment PET‐CT assessment by Deauville criteria is recommended;

however, any treatment decision based on the same needs to be confirmed with a tissue

diagnosis.



REFERENCES

1. Mauz‐Körholz C, Metzger ML, Kelly KM, et al. Pediatric Hodgkin Lymphoma. J Clin Oncol. 2015;33(27):2975‐2985.

2. Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2‐[18f]Fluoro‐2‐deoxy‐d‐glucose positron emission tomography is prognostically superior to international prognostic score in advanced‐stage Hodgkin’s lymphoma: A report from a joint Italian‐Danish study. J Clin Oncol. 2007;25(24):3746‐3752.

3. Gallamini A, Barrington SF, Biggi A, et al. The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five‐point scale. Haematologica. 2014;99(6):1107‐1113.

4. Oki Y, Chuang H, Chasen B, et al. The prognostic value of interim positron emission tomography scan in patients with classical Hodgkin lymphoma. Br J Haematol. 2014;165(1):112‐116.

5. Lopci E, Burnelli R, Ambrosini V, et al. (18)F‐FDG PET in Pediatric Lymphomas: A Comparison with conventional imaging. Cancer Biother Radiopharm. 2008;23(6):681‐690.

6. Paulino AC, Margolin J, Dreyer Z, Teh BS, Chiang S. Impact of PET‐CT on involved field radiotherapy design for pediatric Hodgkin lymphoma. Pediatr Blood Cancer. 2012;58(6):860‐864.

7. Miller E, Metser U, Avrahami G, et al. Role of 18F‐FDG PET/CT in staging and follow‐up of lymphoma in pediatric and young adult patients. J Comput Assist Tomogr. 2006;30(4):689‐694.

8. Levine JM, Weiner M, Kelly KM. Routine use of PET scans after completion of therapy in pediatric Hodgkin disease results in a high false positive rate. J Pediatr Hematol Oncol. 2006;28(11):711‐714.

9. Cheng G, Servaes S, Zhuang H. Value of (18)F‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography scan versus diagnostic contrast computed tomography in initial staging of pediatric patients with lymphoma. Leuk Lymphoma. 2013;54(4):737‐742.

10. Furth C, Steffen IG, Amthauer H, et al. Early and late therapy response assessment with [18F]fluorodeoxyglucose positron emission tomography in pediatric Hodgkin’s lymphoma: analysis of a prospective multicenter trial. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(26):4385‐4391.



11. Ilivitzki A, Radan L, Ben‐Arush M, Israel O, Ben‐Barak A. Early interim FDG PET/CT prediction of treatment response and prognosis in pediatric Hodgkin disease‐added value of low‐dose CT. Pediatr Radiol. 2013;43(1):86‐92.

12. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol Off J Am Soc Clin Oncol. 1989;7(11):1630‐1636.

13. Fryer CJ, Hutchinson RJ, Krailo M, et al. Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low‐dose regional radiation in advanced Hodgkin’s disease in children: a report from the Children’s Cancer Study Group. J Clin Oncol Off J Am Soc Clin Oncol. 1990;8(12):1971‐1980.

14. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579‐586.

15. Barrington SF, Qian W, Somer EJ, et al. Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma. Eur J Nucl Med Mol Imaging. 2010;37(10):1824‐1833.

16. Montravers F, McNamara D, Landman‐Parker J, et al. [(18)F]FDG in childhood lymphoma: clinical utility and impact on management. Eur J Nucl Med Mol Imaging. 2002;29(9):1155‐1165.

17. Depas G, Barsy CD, Jerusalem G, et al. 18F‐FDG PET in children with lymphomas. Eur J Nucl Med Mol Imaging. 2004;32(1):31‐38.

18. Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non‐Hodgkin Lymphoma response criteria. J Clin Oncol. 2015; 33(18):2106‐2111.

19. Friedman DL, Chen L, Wolden S, et al. Dose‐intensive response‐based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate‐risk Hodgkin lymphoma: A report from the Children’s Oncology Group Study AHOD0031. J Clin Oncol. 2014;32(32):3651‐3658.

20. Dinand V, Arya LS. Epidemiology of childhood Hodgkins disease: is it different in developing countries? Indian Pediatr. 2006;43(2):141‐147.

21. Arya LS, Dinand V, Thavaraj V, et al. Hodgkin’s disease in Indian children: outcome with chemotherapy alone. Pediatr Blood Cancer. 2006;46(1):26‐34.



FIGURE 1: Kaplan-Meier graphs for (A, C) EFS and (B, D) OS for (A, B) interim PET-CT (PET (RIW)-2) and (C, D) interim CECT (CT-2). (A) Graph shows EFS according to positive versus negative scan at interim PET-CT based on RIW criteria [PET (RIW)-2]. (B) Graph shows OS according to positive versus negative scan at interim PET-CT based on RIW criteria [PET (RIW)-2].(C) Graph shows EFS according to CR versus no CR at interim CECT (CT-2). (D) Graph shows OS according to CR versus no CR at interim CECT (CT-2).



FIGURE 2: Kaplan-Meier graphs for (A,C) EFS and (B, D) OS for (a, b) post treatment PET-CT (PET (RIW)-3) and (C, D) post treatment CECT (CT-3). (A) Graph shows EFS according to positive versus negative scan at post treatment PET-CT based on RIW criteria [PET (RIW)-3]. (B) Graph shows OS according to positive versus negative scan at post treatment PET-CT based on RIW criteria [PET (RIW)-3].(C) Graph shows EFS according to CR versus no CR at post treatment CECT (CT-3). (D) Graph shows OS according to CR versus no CR at post treatment CECT (CT-3).



FIGURE 3: Kaplan-Meier graphs for (A, C) EFS and (B, D) OS for (A, B) interim PET-CT [PET (Deauville)-2] and (C, D) post treatment PET-CT based on Deauville criteria [PET (Deauville)-3]. (A) Graph shows EFS according to positive versus negative scan at interim PET-CT based on Deauville criteria [PET (Deauville)-2]. (B) Graph shows OS according to positive versus negative scan at interim PET-CT based on Deauville criteria [PET (Deauville)-2].(C) Graph shows EFS according to positive versus negative scan at post treatment PET-CT based on DA criteria [PET (Deauville)-3]. (D) Graph shows OS according to positive versus negative scan at post treatment PET-CT based on Deauville criteria [PET (Deauville)-3].



Table 1: Baseline Characteristics

Characteristic (n = 57) n (%)

Sex

Male 42 (73.6 %)

Female 15 (26.4 %)

Median age (Range) 10 yrs (4‐18 yr)

Stage

Early stage (IA,IB and IIA) 26 (45.6 %)

Advanced stage (IIB –IV) 31 (54.4 %)

Bulky disease 23 (40.3 %)

Median follow‐up (Range) 81.6 months(11‐97.5 months)

Subtype

Mixed cellularity 32 (56.1 %)

Nodular sclerosis 16 (28 .1 %)

Lymphocyte rich 3 (5.2 %)

Lymphocyte depleted 1(1.7 %)

NLPHL 1(1.7 %)

Unspecified 4(7.2 %)

Involved Field radiotherapy 37(64.9)

NLPHL=Nodular lymphocyte predominant hodgkin lymphoma



Table 2: Interim assessment

Parameter CT‐2 (n=56)

PET‐2 (RIW)(n=56)

p value**

PET‐2 (DC)(n=52)

p value***

CR No CR Positive Negative Positive Negative Relapse, (n=4) 1 3 1 3 0 4

Remission (n=52)* 21 31 20 32 4 44

Sensitivity,% (95 % CI) 75 (21.9,98.6)

25 (13.1,78)

0.18 0 (0,60.4)

0.04

Specificity, % (95 % CI) 40.3 (27.3,54.8)

61.5 (47,74.3)

0.03 91.4 (78.7,97.2)

<0.0001

PPV, % (95 % CI) 8.8 (2.3,24.8)

4.7 (0.2,25.8)

0.57 0 (0,60.4)

0.54

NPV, % (95 % CI) 95.4 (75.1,99.7)

91.4 (75.8,97.7)

0.39 91.4 (78.7,97.2)

0.4

RIW= Revised International Working group response criteria, DC=Deauville criteria, CR=Complete response, PPV=Positive predictive value, NPV=Negative Predictive Value, *1 patient who died of pulmonary toxicity (patient 57) was excluded from above analysis **p value calculated for PET‐2(RIW) vs. CT‐2 ***p value calculated for PET‐2(DC) vs. CT‐2

by on May 8, 2018. For personal use only.

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Table 3: Event Free Survival and Overall Survival based on Interim assessment*

Imaging EFS

OS

Estimate±SE 95% CI p‐value


CT‐2(n=57)

0.99

0.82

CR (n=23) 90.6±4.6 81.4,99.8 93.7±3.6 86.5,101

No CR (n=34) 91.1±3.6 84,98.2 93.1±2.9 85.5,98

PET‐2 (RIW)(n=57) 0.44 0.89

Negative (CR) (n=36) 89.6±3.8 82.1,97 93.3±2.8 87.8,98.7

Positive (PR)(n=21) 93.3±4.1 85.2,101.3 93.4±4.0 85.5,101

PET‐2 (DC)(n=53) 0.52 0.61

Negative (CR) (n=49) 89.6±3.4 76.7,95.5 93.±3.4 82,97.9

Positive (PR)(n=4) 100* ‐ 100* ‐

EFS=Event free survival, OS=Overall survival, CR=Complete response, PR=Partial response, RIW= Revised International Working group response criteria, DC=Deauville criteria *There was no relapse in patients with positive PET‐2(DC)


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Table 4: Post treatment assessment

Parameter CT‐3(n=55)

PET‐3 (RIW)(n=54)

p value**

PET‐3 (DC)(n=51)

p value***

No CR CR Positive Negative Positive Negative Relapse, (n=4) 1 3 1 3 1 3

Remission (n=51)* 12 39 6 44 2 45

Sensitivity ,% (95 % CI) 25 (13.1,78)

25 (13.1,78)

1 25 (13.1,78)

1

Specificity, % (95 % CI) 76.4 (62.1,86.7)

88 (74.9,95) 0.11 95.7 (84.2,99.2)

0.006

PPV, % (95 % CI) 7.6 (0.4,37.9)

14.2 (0.7,57.9)

0.27 33.3 (1.7,87.4)

0.23

NPV, % (95 % CI) 92.8 (79.4,98)

93.6 (81.4,98.3) 0.86 94.1 (82.7,98.4)

0.78

RIW= Revised International Working group response criteria, DC=Deauville criteria, CR=Complete response, PPV=Positive predictive value, NPV=Negative Predictive Value *1 patient who died of pulmonary toxicity (patient 57) was excluded from above analysis **p value calculated for PET‐3(RIW) vs. CT‐3 ***p value calculated for PET‐3(DC) vs. CT‐3


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Table 5: Event Free Survival and Overall Survival based on post treatment assessment

Imaging EFS OS



CT‐3 (n=56) 0.90 0.67

CR(n=43) 91.0±3.2 84.7,97.3 94.1±2.3 89.5,98.8

No CR(n=13) 87.4±6.3 75,99.8 87.6±6.1 75.6,99.6

PET‐3 (RIW) (n=55)

0.58 0.27

Negative (CR)(n=48) 91.7±2.9 86,97.4 94.5±2.1 90.3,98.7

Positive(PR/PD)(n=7)

84.1±11.6 61,107 84.5±11.3 62.3,106.7

PET‐3 (DC)(n=52) 0.094 0.029

Negative (CR)(n=49) 91.8±2.8 86.2,97.4 94.5±2.0 90.5,98.6

Positive(PR/PD)(n=3)

65.5±23.2 20,111.1 66.4±22.5 22.2,110

EFS=Event free survival, OS=Overall survival, CR=Complete response, PR=Partial response, PD=Progressive disease, RIW= Revised International Working group response criteria, DC=Deauville criteria


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SUPPLEMENTARY FIGURE 1: Baseline PET-CT image of patient no. 48 who had involvement of cervical , mediastinal and retroperitoneal lymph nodes and spleen involvement (A,B) with additional involvement of liver (arrow in C) and bone marrow (arrow in B) not detected CECT (D). (Upstaging at baseline).



SUPPLEMENTARY FIGURE 2: PET-CT image of patient 53 at baseline (A, D, G), interim (B, E, H) and end of treatment (C, F, I) showing interim PET-CT positivity by both RIW and Deauville criteria in lung and right cervical lymph node (arrows) which have resolved at the end of treatment (False positive interim PET).



SUPPLEMENTARY FIGURE 3: PET-CT image of patient no 17 at baseline (A, D, G), interim (B, E, H) and end of treatment (C, F, I) which was Deauville score 3 (CR) at interim assessment with Deauville criteria and Deauville score 5 (C, F, I) in retroperitoneal lymph nodes (arrows) which was negative in previous scan (B, E, H) (True Positive at end of treatment).



SUPPLEMENTARY FIGURE 4: PET-CT image of patient no 21 at end of treatment showing PET-CT positivity at mediastinal lymph node (arrows in A, B ,C) which was positive for tuberculosis on biopsy. Patient received anti-tubercular therapy and is disease free at last follow up (False positive at end of treatment).



Supplementary Table 1: Baseline staging, response and follow up in study patients

Patient No

CT Stage

PET Stage

Cause for upstaging/ downstaging*

CT- 2

PET/CT-2 (RIW)

PET/CT -2 (DC)

CT-3 PET/CT-3 (RIW)

PET/CT-3 (DA)

Outcome RT

1 2 4 Uptake in bone marrow PR PR PR CR CR NA Alive at 94.4 months Yes 2 1 1 - CR PR PR CR CR CR Alive at 94.2 months Yes 3 3 3 - PR CR CR CR CR CR Alive at 84.2 months Yes 4 1 1 - PR CR CR CR CR CR Alive at 86.2months Yes 5 3 3 - PR PR NA PD PD NA Alive at 86.5months - 6 3 2 No uptake in RPLN PR CR CR CR CR CR Alive at 90.7 months - 7 1 3 Uptake in RPLN, spleen PR CR CR CR PD CR Alive at 87.7months Yes 8 2 2 - PR PR PR PR CR CR Alive at 90.0 months Yes 9 2 2 - PR CR CR CR CR CR Alive at 90.2 months Yes 10 3 3 - PR PR NA CR PR CR Alive at 90.4 months - 11 2 2 - CR CR CR CR CR CR Alive at 90.5 months Yes 12 1 2 Uptake in mediastinal LN PR CR CR PR CR CR Alive at 90.6 months Yes 13 2 1 Uptake only in right cervical LN PR CR CR PR CR CR Alive at 91.8 months Yes 14 3 3 - PR PR PR CR PR CR Alive at 92.1 months Yes 15 3 4 Uptake in bone marrow PR PR CR CR CR CR Alive at 95.6 months Yes 16 2 2 - CR PR PR CR PR CR Alive at 96.7 months Yes 17 4 4 - PR PR PR PD PD PD Relapse at 8.6 months

Died at 11.2 months Yes

18 1 3 Uptake in RPLN, spleen PR CR CR CR CR CR Alive at 97.3 months Yes 19 4 4 - CR PR PR CR CR CR Alive at 97.5 months - 20 1 4 Uptake in vertebrae, spleen PR CR CR NA NA NA Alive at 94.4 months Yes 21 2 3 Uptake in mediastinal LN PR CR CR PR PD PD Alive at 94 months - 22 1 1 - CR CR CR CR CR CR Alive at 94 months Yes 23 1 1 - CR CR CR CR CR CR Alive at 92.9 months Yes 24 1 1 - CR PR NA CR CR CR Alive at 90.9 months Yes 25 2 2 - PR PR CR PR CR CR Alive at 43.9 months - 26 1 2 Uptake in bilateral cervical LN PR CR CR CR CR CR Alive at 85.1 months Yes 27 2 2 - CR CR CR CR CR CR Alive at 81.6 months Yes 28 2 4 Uptake in spleen, bone marrow PR CR CR CR CR CR Alive at 64.2 months - 29 4 4 - PR PR PR CR CR CR Alive at 82.3 months - 30 1 1 - PR CR CR CR CR CR Relapse at 65 months

Alive at 80.2 months Yes

31 2 2 - CR CR CR CR CR CR Lost to follow up after 18 months

-

32 1 1 - PR CR CR CR CR CR Alive at 80.2 months Yes 33 3 2 No uptake in RPLN CR PR NA CR CR CR Alive at 44.1 months - 34 2 3 Uptake in spleen PR CR CR PR CR CR Alive at 80.5 months Yes 35 2 3 Uptake in cervical, mediastinal LN PR CR CR CR CR CR Relapsed at 11 months

Died at 41.4 months -

36 3 3 - CR CR CR CR CR CR Relapse at 28 months Alive at 74.8 months

-

37 3 4 Uptake in left pelvic bone PR CR CR CR CR CR Alive at 81.3 months - 38 3 3 - CR CR CR CR CR CR Alive at 74.3 months - 39 1 3 Uptake in mediastinum, spleen CR CR CR CR CR CR Alive at 76 months Yes 40 4 4 - CR CR CR CR CR CR Alive at 76.9 months - 41 2 2 - CR CR CR CR CR CR Alive at 76.2 months Yes 42 4 4 - PR CR CR CR CR CR Alive at 75.8 months - 43 4 4 - CR CR CR CR CR CR Alive at 77.2 months - 44 2 3 Uptake in RPLN CR CR CR CR CR CR Alive at 79.1 months Yes 45 2 3 Uptake in RPLN, spleen PR PR PR CR CR CR Alive at 78.6 months Yes 46 2 3 Uptake in spleen PR PR CR PR CR CR Alive at 73.6 months Yes 47 2 1 Uptake only in right cervical LN CR CR CR CR CR CR Alive at 73.2 months Yes 48 3 4 Uptake in bone marrow, liver PR PR PR PR NA NA Alive at 72.9 months - 49 1 1 - CR CR CR CR CR CR Alive at 71.1 months Yes 50 1 3 Uptake in RPLN, spleen PR CR CR PR CR CR Alive at 73.9 months Yes 51 4 4 - PR CR CR PR CR CR Alive at 69.9 months Yes 52 3 3 - CR PR CR CR PD PD Alive at 72.7 months - 53 3 4 Uptake in lung, vertebrae PR PR PR PR CR CR Alive at 60.5 months Yes 54 1 2 - CR CR CR CR CR CR Alive at 94.7 months Yes 55 1 3 Uptake in RPLN, spleen CR PR CR CR CR NA Alive at 87.9 months Yes 56 2 3 Uptake in left cervical LN PR PR PR CR CR CR Alive at 84.8 months - 57 2 3 Uptake in RPLN, spleen CR CR CR CR CR CR Died at 11 months due

to pulmonary toxicity Yes

*Additional sites of involvement seen on PET-CT or only site of involvement in case of down staging are shown. LN-lymph node, RPLN- retroperitoneal lymph node, RIW= Revised International Working group response criteria, DC-Deauville criteria, RT- Radiotherapy, CR-Complete response, PR-partial response



Doi: 10.2967/jnumed.116.176511Published online: October 6, 2016.J Nucl Med. Malhotra, Deepa Dhawan and Sreenivas VishnubhatlaSameer Bakhshi, Sainath Bhethanabhotla, Rakesh Kumar, Krishankant Agarwal, Punit Sharma, Sanjay Thulkar, Arun versus Conventional ImagingOutcome in Pediatric Hodgkin Lymphoma: a Prospective Study Comparing PET-CT Post-treatment PET-CT Rather than Interim PET-CT Using Deauville criteria Predicts

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